This program project grant is designed to integrate the activities of 4 projects and 4 core facilities toward potentiating the overall goal of this PPG which is to discover selective tumor vascular targets and to develop and test tumor vascular targeting agents for cancer treatment. Each of the projects involves a strategy designed to target vessels associated with solid cancer tissue. Studies which have been carried out to date reveal that the cell surface of blood vessels associated with tumor tissue contain proteins which are not found on the surface of vessels of normal tissues. These differences may be caused by angiogenic and other trophic factors that are released by tumor cells in the vicinity of the endothelial cells and that induce proliferation of the endothelial cells with poor vessel remodeling. The cancer center has developed a unique concentration of investigators avidly interested in tumor vascular biology and dedicated to translating lab bench discoveries to clinical applications at the patient's bedside. Targeting of the tumor vasculature can accomplish two very important goals by generating: i) a new and more sensitive imaging diagnostic tool for the early detection of cancer and ii) a new modality of site-directed therapy for cancer that permits better access and effectiveness in vivo and that avoids the evolution of resistance. In addition to these applied goals, this program project grant will deepen our understanding of the mechanisms in the tumor neovasculature governing drug efficacy, induction of apoptosis, caveolae function, and proliferation of endothelial cells. The integration of the projects and the cores is designed not only to demonstrate the specificity of the binding of tumor-homing peptides, proteins and antibodies to the endothelial cell surface of the tumor vasculature, but also to understand what are the cell biological events which occur following binding including possible trafficking into the endothelium and beyond to the tumor cells as well as the mechanisms by which tumor cell death and vessel occur following binding. The cores provide an unique opportunity to utilize total body imaging to track targeting in vivo, intravital microscopy to study mechanisms and specificity at the tissue level, and light, fluorescence confocal and electron microscopy to define target localization and to follow probes directed to, and incorporated into, the tumor at the cellular and subcellular level. The administrative core will promote the integration of the projects and cores over 3 local institutions: SKCC, The Scripps Research Institute, and The Burnham Institute in San Diego as well as Yale University School of Medicine in New Haven, CI. The integrative potentiation of each project may lead to new strategies, including single and combined therapies for clinical translation in the future.